Chronic pain development may involve the generalization and strengthening of acute pain memories (Moseley and Vlaeyen, 2015). Neuronal encoding of painful stimuli, known as nociception, is an evolutionarily conserved, unconditioned response (UCR) generated upon exposure to a tissue-damaging unconditioned stimulus (UCS). When pain persists, subjects are either repeatedly presented with or chronically experiencing this UCS, providing opportunity for various external cues or conditioned stimuli (CS) to become associated with the UCS. Pairings of the painful UCS with external cues can eventually lead to the development of a conditioned response (CR) elicited by the CS alone. In this way, nociceptive signaling and resulting pain behaviors may be modulated by previously biologically irrelevant stimuli.

Pavlov, 2010, was the first to describe the process through which a biologically irrelevant stimulus could come to exert control over physiological processes in a way that allows the organism to prepare for the upcoming disruption of homeostasis produced by the UCS. In addition to auditory stimuli like those used in Pavlov’s experiments, the immediate environment or ‘context’ may control these preparatory responses as was demonstrated in an important experiment performed by Siegel et al., 1982. Over the course of 15 days, Siegel et al. treated rats with escalating doses of a mu-opioid receptor agonist (heroin) in one distinct physical environment. After training, animals received an ostensibly lethal dose of heroin (96.4% mortality rate in heroin-naïve rats) in the same environment where training occurred, or in a separate, novel environment. When administered in a novel context, this dose of heroin killed 64.3% of animals; the same amount of heroin administered in the familiar context decreased the death rate by ~50% such that only 32.4% of animals died. Similar to the CR first reported by Pavlov, 2010, this work suggested that the familiar environment served as a CS that predicted upcoming heroin administration, thereby initiating internal processes associated with drug tolerance. This phenomenon has since been termed a ‘conditioned compensatory response’ as exposure to the CS begins the process of compensating for the upcoming drug effect (see also Siegel, 1977; see Siegel et al., 2000, for a review). Here, we used a similar experimental paradigm to determine if repeated exposure to an acute painful stimulus in a specific context affects sensitivity to that stimulus. In other words, do animals exhibit conditioned compensatory responses to painful stimuli? And if they do, what is the physiological basis of that response?

It is also well documented that context can exert control over learned behaviors related to fear and anxiety (Bouton and Bolles, 1979) as well as over instrumental and choice behaviors (Trask and Bouton, 2014). Recently, context was found to influence pain behaviors in male mice and humans after a single conditioning trial (Martin et al., 2019). Both male mice and men exhibited stress-induced hyperalgesia if tested in an environment previously associated with a painful stimulus (Martin et al., 2019). Similarly, in a place avoidance task, male mice avoided the environment previously associated with this same noxious UCS (Martin et al., 2019). Neither female mice nor women exhibited conditioned hypersensitivity, conditioned place aversion, or context-dependent increases in circulating stress hormones in these experiments, suggesting that context did not impact nociceptive signaling in females as it did in males. However, an alternative interpretation of these data may be that contextual cues engaged compensatory endogenous analgesic systems in females, even in the absence of ongoing pain, such that their pain behaviors pre- and post-conditioning were indistinguishable. This hypothesis is appealing given the potential therapeutic implications that could follow if environment is capable of modulating endogenous analgesic mechanisms. To date, the few studies that have examined environmental influence on conditioned analgesia have primarily done so in fear conditioning paradigms. In general, those studies found that following fear conditioning in which a CS predicts an aversive shock outcome, animals exhibited increased pain tolerance (i.e., conditioned hypoalgesia) in the environment, or context, where fear conditioning occurred (Fanselow and Helmstetter, 1988; Harris and Westbrook, 1994; Harris and Westbrook, 1995; Helmstetter and Fanselow, 1987; Watkins et al., 1993). Although the conditioned fear responses exhibited following this associative learning have been extensively studied, the potential compensatory analgesic responses produced by context exposure have received little to no attention outside of these paradigms. We therefore designed a novel set of experiments to determine if context could be used as a CS to engage endogenous analgesic mechanisms and thus increase pain tolerance, in the absence of overt fear conditioning or ongoing pain.

In the present set of experiments (see Figure 5 for a summary), we asked whether environment can exert control over pain sensitivity and pain expectation through associative learning. We first demonstrated, in a within-subject manner, that a context (CS) paired with a painful experience (acetic acid injection; UCS) can induce conditioned analgesia in animals upon re-exposure to the CS. Although female mice demonstrate this conditioned analgesia after pairing a relatively weak UCS with the CS, male mice only develop conditioned analgesia if a stronger UCS is used throughout conditioning trials. We then determined that this effect is likely not mediated by stress, but rather by activation of the endogenous opioid system since administration of the opioid antagonist naloxone blocked conditioned analgesia in both sexes. In a second set of experiments, we demonstrated that males exhibit conditioned hypersensitivity when placed into a context previously associated with pain. Alternatively, females exhibit conditioned analgesia that is dependent on endogenous opioid signaling when placed into a similar environment. Together, these results demonstrate that context can come to exert control over the endogenous opioid system such that it is recruited as a conditioned compensatory response to ongoing painful stimuli in both sexes, or in anticipation of a painful stimulus in females.

Figure 5

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In the ongoing search for better/novel analgesics, many preclinical biologists, including some of the present authors, have taken a reductionist approach using highly standardized in vitro or in vivo assays to determine how particular genes or proteins contribute to the process of nociception. In so doing, significantly less has been learned about the influence external factors have on pain perception and the development of chronic pain. In their ‘Imprecision Hypothesis’ (2015), Moseley and Vlaeyen posit that chronic pain may develop, in part, as a result of associative learning; repeated coupling of a UCS – in this case a noxious input – with neutral cues like a specific movement of the body (e.g., bending over) or context may lead to the perception of pain (CR) upon subsequent presentation of these newly CS. Data presented in this manuscript are, to our knowledge, the first preclinical test of this hypothesis; we repeatedly paired noxious visceral stimulation (i.e., IP acetic acid injection; UCS) with a unique context (i.e., a behavior chamber; CS). Similar to the results obtained following a single pairing of this same UCS and CS (Martin et al., 2019), male mice developed conditioned hypersensitivity upon CS presentation alone (Figure 4B). In contrast, when females are exposed to the CS, they engage their endogenous opioid system, such that behavioral responses appear similar to those exhibited prior to injury or conditioning (Figure 4C). These divergent results suggest there are qualitative sex differences in the biological processes that mediate pain expectation.

The biological basis and evolutionary explanation for these qualitative sex differences is currently unknown. Dimorphisms in endogenous opioid circuit anatomy and function are well documented (Chakrabarti et al., 2010; Liu et al., 2007; Loyd and Murphy, 2006; Loyd et al., 2008; Tershner et al., 2000). Perhaps adaptive pressures associated with the reproduction timeframe and energy requirement led to differential abilities to recruit endogenous opioid signaling such that female organisms are better able to activate this system as a means of dampening ongoing pain. Another intriguing hypothesis is that brain regions required for contextual conditioning – like the dorsal hippocampus (Maren and Holt, 2004; Matus-Amat et al., 2004) and retrosplenial cortex (Keene and Bucci, 2008; Kwapis et al., 2015; Miller et al., 2021; Trask et al., 2021) – and those involved in descending pain inhibition are differentially connected in each sex. For example, electrical stimulation of the retrosplenial cortex decreases both formalin-associated spontaneous pain (Reis et al., 2010) and post-surgical mechanical hypersensitivity (Rossaneis et al., 2011) by modulating opioid signaling in the anterior pretectal nucleus (Rossaneis et al., 2011). Because only male rats were used in these studies, it is unclear (1) if this circuit functions similarly in female rodents, (2) if this circuit is engaged during contextual conditioning, and (3) if the retrosplenial cortex, or other structures important for contextual learning, differentially projects to other brain regions associated with endogenous analgesia modulation in the two sexes.

In addition to assessing pain expectation, we also examined if associative learning impacts pain sensitivity, or the magnitude of the UCR elicited by a noxious stimulus. The UCS used in these experiments was IP injection of acetic acid, a procedure that induces reflexive writhing behaviors (Koster et al., 1959). In addition to writhing, hindpaw mechanical sensitivity testing was used as a second UCR to examine a behavioral output that, by definition in this experimental paradigm, is modulated by descending control. Recently, Tansley et al., 2019, characterized a phenomenon in which pain in one part of the body causes hyperalgesia in an anatomically separate body region if evoked with a relatively mild noxious stimulus. In contrast to the ‘pain-inhibits-pain’ idea associated with the electrophysiological phenomenon known as DNIC, this observation which has been called ‘anti-DNIC’, facilitatory CPM, or ‘hyperalgesic DCN’ is observed across multiple rodent species and mouse strains and does not depend on the anatomical proximity of the injured and test sites. Despite initially demonstrating hyperalgesic DCN, both male and female mice in the present experiments developed conditioned analgesia after repeated exposure to the noxious stimuli; both sexes exhibited less pain when presented with a noxious UCS in an environment (CS) associated with an acute pain memory (Figure 2B and C). Notably, however, there was a quantitative sex difference in the strength of the UCS required to develop this conditioned pain tolerance; male mice only developed conditioned pain tolerance if trained with high doses of acetic acid. Strength of conditioning also influenced whether conditioned analgesia was observed in writhing behaviors. Context (CS) had no effect on writhing behaviors except in female mice trained with high doses of acetic acid (Figure 2F). Conditioned analgesia was not observed in writhing data collected from female mice trained with lower doses of acetic acid, or male mice trained with high or low doses of acid. One potential explanation for the observed differences in writing and hindpaw withdrawal behaviors is that writhing may reflect the reflexive unconditional response to acetic acid (analogous to rodent jumping in response to a shock presentation; animals habituate to stimuli with repeated presentations) whereas the sensitivity of the hindpaw might be a more direct assessment of pain expectancy (analogous to freezing to a tone previously paired with shock). Regardless, these data reiterate the idea that females are particularly sensitive to, and thus able to associate, external cues more strongly with visceral pain stimuli. This is perhaps unsurprising given the extensive literature describing sex differences in pain perception.

The idea that males and females perceive pain differently is a long-standing topic in both academic and popular science discussions. Upon review of this topic, it is clear that women are more sensitive to acute pain stimuli than men, and that chronic pain is more frequently reported in women than it is in men (Mogil, 2012; Mogil, 2020). Rodent data presented in this paper agree with this conclusion; female mice exhibited more pain than male mice following low (0.1%; Figure 1D) and high (0.9%; Figure 2D) acetic acid administration. Similar quantitative sex differences have been previously reported in other visceral pain models. For example, male and ovariectomized female rodents are less sensitive to chemical or mechanical injury of the colon and urinary bladder (reviewed by Traub and Ji, 2013). Combined with the fact that stronger UCS will support more conditioning to stimuli presented with those UCS (Holland, 1979; Morris and Bouton, 2006; see Rescorla and Wagner, 1972), the present results suggest that females more readily associate contextual cues with noxious visceral stimuli because they perceive visceral pain more intensely than males. Under this logic, females should develop conditioned analgesia more quickly than males if the same noxious stimulus is used to train both sexes. In support of this hypothesis, six of eight female mice included in Figure 2 exhibited conditioned analgesia on day 2 of the paradigm (i.e., higher paw withdrawal thresholds in the acid-paired chamber on day 2 vs. day 1) whereas zero of the eight male mice in this same study exhibited conditioned analgesia on day 2 (Figure 2—figure supplement 1). An additional interpretation of the present results is that the visceral pain introduced via acetic acid injection created a secondary internal context that males are unable to generalize. A wide variety of internal states have been shown to serve as contextual stimuli that influence behavioral performance (Garfinkel et al., 2021; Schepers and Bouton, 2017; Schepers and Bouton, 2019; see Bouton, 1991). Under this interpretation, the present results, in which males show conditioned hypersensitivity when placed into the acid-paired context without the UCS, might be explained by a lack of generalization as only the exteroceptive, but not interoceptive, context is the same as that which was included in training. While this seems unlikely to explain all results, interoceptive contexts might have played a role in the current design.

Strength of conditioning, or lack of UCS generalization, may also have influenced whether conditioned hyperalgesia or analgesia was displayed in the training context in the absence of the UCS. For example, after one pairing of 0.9% acetic acid and context, male mice exhibit conditioned hypersensitivity (Martin et al., 2019) whereas females, based on the observations made in these studies, likely exhibit conditioned analgesia. Would females exhibit conditioned hypersensitivity if trained with a single exposure to 0.1% acetic acid? Would males exhibit conditioned analgesia if trained with more than three exposures to 0.9% acetic acid? Experiments of this nature would allow for the classification of these sex differences as qualitative or quantitative. To this end, it is also important to clarify how long conditioned analgesia/hyperalgesia last in the absence of further conditioning and to determine the stimulus intensity and frequency required to maintain conditioning. Answers to these questions might allow for better explanations as to why chronic pain is more prevalent in females than males and provide opportunities to develop pain therapies based on associative learning principles. Although the opportunity for maladaptive learning exists, females may be better prepared, biologically speaking, to associate relief of ongoing pain with CS than males. Confirmation of this hypothesis may lead to the development of novel cognitive therapeutic strategies for pain that rely on the principles of Pavlovian conditioning, or those related to other memory-based manipulations like reframing (Pavlova et al., 2022). However, these approaches should be developed with caution. In the present study, mice were exposed to only novel CS and UCS. It is a well-documented finding that previous exposure to a putative CS makes it more difficult to become predictive of a UCS (termed ‘latent inhibition’; e.g., Lubow, 1973). In cases of chronic pain development in humans, it is rarely the case that either the environment or the chronic pain are inherently novel, and thus, this type of conditioning would likely take longer to develop than in the procedure employed here.

In conclusion, the data presented here demonstrate that context can control pain perception while an animal is actively experiencing pain or when an animal is anticipating a painful experience. These results are evidence that pain perception and engagement of endogenous opioid systems can become dependent on the environment for expression and can be modified through their psychological association with environmental cues. Future work will examine the neural pathways associated with the contextual control of pain processing including those that mediate opioid release in response to pain-associated environments. Further, additional studies will need to examine if continuous chronic pain is susceptible to the effects of conditioning observed here.

All data generated or analyzed during this study are included in the manuscript.

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Author details

1. Sydney Trask

   Department of Psychological Sciences, Purdue University, West Lafayette, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Visualization, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4396-5334

2. Jeffrey S Mogil

   Department of Psychology and Anesthesia, Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada

   Contribution

   Conceptualization, Supervision, Writing - review and editing

   Competing interests

   No competing interests declared

3. Fred J Helmstetter

   Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, United States

   Contribution

   Supervision, Writing - review and editing

   Competing interests

   No competing interests declared

4. Cheryl L Stucky

   Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States

   Contribution

   Supervision, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4966-6594

5. Katelyn E Sadler

   Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Visualization, Writing - original draft, Writing - review and editing

   For correspondence

   ksadler@mcw.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2078-3527

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